Many diseases, deficiencies and conditions can be treated by supplying to the patient one or more biologically active factors produced and/or secreted by living cells. In many cases, these factors can restore or compensate for the impairment or loss of organ or tissue function.
However, the impairment or loss of organ or tissue function may result in the loss of multiple metabolic functions. For example, it has been reported that in fulminant hepatic failure, liver tissue is rendered incapable of removing toxins, excreting the products of cell metabolism, and secreting essential factors, such as albumin and Factor VIII (Bontempo, et al., Blood, 69, pp. 1721-1724 (1987)).
In many diseases or conditions, the affected organ or tissue is one which normally functions in a manner responsive to the physiological state, by, for example, responding to fluctuations in the levels of specific metabolites and/or physiologically important substances, thereby maintaining homeostasis. Traditional factor supplementation therapy cannot compensate for the responsiveness of the normal tissue to these fluctuations and failure to provide such attuned responsiveness to the physiological state may lead to complications of the disease state.
Accordingly, many investigators have attempted to reconstitute organ or tissue function by transplanting whole organs or organ tissue to provide secreted products or effect metabolic functions. For example, liver transplantation is the established therapy for end-stage liver disease, as described by Starzl, et al., N. Eng. J. Med. 321:1014-1022 (1989). In another example, patients with hemophilia A have undergone liver transplantation as a result of liver failure resulting from hepatitis acquired from the blood derived factor VIII. In these instances, there has been a complete cure of the hemophilia. However, transplantation therapy is limited in its application by the scarcity of organs available for transplantation. For example, it has been reported that more than 25,000 people die each year in the United States of liver disease (Murphy, S L. Deaths: final data for 1998. Natl. Vital Stats. Rep. 2000; 48:1-105), and 11% of those listed for transplantation in 2001 died while waiting for an organ (Annual report of the U.S. Organ Procurement and Transplant Network and the Scientific Registry of Transplant Recipients, 2003).
In general, the patient must undergo immunosuppression or immunomodulation in order to avert immunological rejection of the transplant, which results in loss of transplant function and eventual necrosis of the transplanted organ or tissue. However, immunosuppressive or immunomodulatory therapy generally impairs the patient's overall immunological defences, which may increase susceptibility to the risks of a variety of serious complications, including nephrotoxicity, neurotoxicity, hypertension, increased susceptibility to infection and osteoporosis. Moreover, this approach is not always effective in altering the course and incidence of rejection episodes. Typically, the transplant must remain functional for a long period of time, even for the remainder of the patient's lifetime. It is both undesirable and expensive to maintain a patient in an immunosuppressed or immunomodulated state for a substantial period of time.
Transplanted cells may provide greater potential for treating various diseases as such cells can provide factors to replace or supplement natural factors which, due to their insufficiency or absence, cause disease. Cell implantation therapy has an advantage over traditional factor-supplementation therapy regimens as the transplanted cells can respond to fluctuations in the levels of specific metabolites and/or physiologically important substances in the recipient. The release of therapeutic factors from the transplanted cells may be properly regulated provided the transplanted cells have the necessary receptors and ability to respond to endogenous regulators.
Cell implantation therapy has an advantage over traditional organ transplantation therapies in that the availability of cells suitable for implantation is not limited as are suitable organs from cadaveric or live organ donors.
In addition, whilst cells which are to be implanted may be foreign to the host, various methods have been developed to prevent the host immune system from attacking and thereby causing the death of the implanted cells, such as, for example, placing cells in devices that provide a physical barrier between the cells and the host's immune system.
However, the isolation and culture of hepatocytes for implantation to secrete Factor VIII and other liver secretory factors, is difficult as hepatocytes are easily damaged and difficult to culture. Their long term culture and efficacy once implanted are therefore not fully characterised.
It would therefore be desirable to have a method for the long term culture of hepatocytes and other non-hepatocytes which are capable upon implantation into a patient, of secreting liver secretory factors, whereby the method results in robust cells which are suitable for long term implantation. It would also be desirable to have a method for producing Factor VIII and other liver secretory factors from cells other than hepatocytes and which are suitable for implantation in a patient in need thereof.
It is an object of the invention to go some way towards achieving these desiderata and/or to provide the public with useful choice.